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Supplementary Data from Mutational Analysis of 472 Urothelial Carcinoma Across Grades and Anatomic Sites

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posted on 2023-03-31, 21:24 authored by Amin H. Nassar, Renato Umeton, Jaegil Kim, Kevin Lundgren, Lauren Harshman, Eliezer M. Van Allen, Mark Preston, Fei Dong, Joaquim Bellmunt, Kent W. Mouw, Toni K. Choueiri, Guru Sonpavde, David J. Kwiatkowski

Histogram showing the distribution of alterations in KDM6A in males and females for 4 subtypes of urothelial carcinoma. Red bars are scaled to show the frequency (%) of female samples with an alteration in KDM6A; Gray bars are scaled to show the frequency of bi-allelic mutation in KDM6A in female samples; and blue bars show the frequency of KDM6A mutation in males. The numbers above each bar indicate the number of samples with each category of alteration; the numbers below show the total number of samples for each sex and UC subtype.

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ARTICLE ABSTRACT

The purpose of this study is to characterize the mutational landscape across the spectrum of urothelial carcinoma (UC) to identify mutational features and potential therapeutic targets. Using targeted exome sequencing (n = 237 genes), we analyzed the mutation spectra of 82 low-grade nonmuscle-invasive bladder cancers (LG-NMIBC), 126 high-grade (HG) NMIBC, 199 muscle-invasive bladder cancers (MIBC), 10 LG-upper tract urothelial cancers (LG-UTUC), and 55 HG-UTUC. FGFR3 and KDM6A mutations were significantly more common in LG-NMIBC (72% and 44%, respectively) versus other bladder subtypes. FGFR3 alterations were also enriched in LG-UTUC versus HG-UTUC tumors (80% vs. 16%). In contrast, TP53 and RB1 mutations were significantly more frequent in all 3 HG urothelial carcinoma subtypes than in LG-NIMBC (45%–58% vs. 4%; 9%–22% vs. 0; respectively). Among LG-NMIBC tumors, KDM6A mutations were more common in women than in men (71% vs. 38%). HG-NMIBC and MIBC had higher tumor mutational burden (TMB) than LG-NMIBC (P = 0.001 and P < 0.01, respectively). DNA-damage repair (DDR) alterations were associated with a higher TMB in HG-NMIBC and MIBC tumors, and these two tumor types were also enriched for an APOBEC mutational signature compared with LG-NMIBC and HG-UTUC. Alterations in FGFR3, PIK3CA, and EP300 correlated with worse overall survival in HG-UTUC and occurred concurrently. Our analysis suggests that a fraction of MIBCs likely arise from precursor lesions other than LG-NMIBC. KDM6A mutations are twice as common in women with LG-NIMBC than those in men. DDR gene mutations and APOBEC mutagenesis drive mutations in HG-NMIBC and MIBC. UTUC has a distinct mutation profile from bladder cancer.

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